Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[CH:24][NH:25]2)=[CH:21][CH:20]=1.[OH-].[Na+]>O1CCOCC1>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:27]=[C:26]4[C:22]([CH:23]=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cc[nH]c4c3)ncn2)cc1
Temperature: 25 °C

Procedure:
To a 100-mL, round-bottomed flask containing 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.20 g, 0.77 mmol) and 6-hydroxyindole (0.21 g, 1.5 mmol, Aldrich) in 1,4-dioxane (10 mL), was added NaOH (8.0 mL, 8.0 mmol, 1.0 N). The mixture was heated at reflux for 8 h, and after cooling to room temperature, the reaction mixture was concentrated in vacuum. EtOAc (30 mL) was added, and the organic layer was washed with brine (10 mL), water (15 mL), dried over Na2SO4, filtered, and concentrated in vacuum. After the product was purified by silica gel chromatography (5:1 hexanes/EtOAc), the residue was dissolved in acetone (3 mL). Water (4 mL) was then added dropwise to afford a white precipitate, which was collected by filtration, washed with water (0.5 mL), and dried under vacuum at 50° C. for 48 h to furnish the title compound. Mp: 206-209° C. MS (ESI, pos. ion) m/z: 356 (M+1); Anal. Calcd for C19H12F3N3O·(H2O)0.2: C, 63.58; H, 3.48; N, 11.71. Found: C, 63.82; H, 3.37; N, 11.61
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>ClCCl>[C:38]1([O:37][C:35]([N:15]2[CH2:14][CH2:13][N:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:9]([Cl:8])[C:10]([C:24](=[O:25])[NH2:26])=[C:11]3[CH2:16]2)=[O:36])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CN(C(=O)Oc1ccccc1)CC2
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A suspension of 7-chloro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (100 mg, Reference Example 1) in dry dichloromethane (5 mL) was treated with dry triethylamine (0.11 mL). The resulting solution was then cooled to −40° C. and treated with a solution of phenyl chloroformate (32 μL, redistilled) in dry dichloromethane (5 mL) whilst maintaining the temperature at 40° C. After stirring at −40° C. for a further 30 minutes the reaction mixture was allowed to warm to room temperature and then washed three times with water (20 mL). The organic phase was dried over magnesium sulfate and the solvent then removed under reduced pressure. The residue was subjected to column chromatography on silica eluting with a mixture of pentane and ethyl acetate (9:11, v/v) to give 8-carbamoyl-7-chloro-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid phenyl ester (40 mg) as a white solid, m.p. 196–198° C. [Elemental analysis: C, 63.52; H, 4.45; N, 10.31%; Calculated for C21H18ClN3O3: C, 63.72; H, 4.58; N, 10.62%].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.O>C1COCC1>[F:12][C:2]([F:1])([F:11])[C:3]1[N:8]=[C:7]([NH:9][NH:10][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([F:13])=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NNc1cccc(C(F)(F)F)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNc1cccc(C(F)(F)F)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.4 %

Procedure:
To a stirred solution of 6-(trifluoromethyl)pyridin-2-ylhydrazine (3.00 g, 16.4 mmol) and 4-fluorobenzoyl chloride (2.95 g, 18.63 mmol) in anhydrous THF (20 mL) at 0° C. under N2 was added diisopropylethylamine (2.41 g, 18.63 mmol). After 15 min, the solution was allowed to warm to room temperature over 1 h. Water (80 mL) was added, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic extracts were combined, washed with water (100 mL), dried over MgSO4, and concentrated in vacuo to a tan solid. Recrystallization from ethyl acetate afforded the title compound of Step A as a white solid (3.16 g). 1H NMR (Me2SO-d6, 400 MHz) δ10.55 (s,1H), 9.10 (s, 1H), 8.00 (m,2H), 7.80 (t, 1H), 7.40 (t,2H), 7.15 (d, 1H), 6.90 (d, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]1[O:31][N:30]=[C:29]([CH:32]=O)[CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:32][C:29]3[CH:28]=[C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)[O:31][N:30]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=Cc1cc(-c2cccs2)on1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2cc(-c3cccs3)on2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To 10 mL of a chloroform solution containing 407 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 275 mg of 5-(2-thienyl)-3-isoxazolecarbaldehyde, 80 μL of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 468 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=2:1], to give 232 mg of 7-fluoro-1-(2-(4-((5-(thiophen-2-yl)isoxazol-3-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as pale yellow solid.
Reaction SMILES: [Cl:1][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[Na+].[I-]>CO>[ClH:1].[CH:14]([C:6]1[C:5]([C:3](=[O:4])[CH:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:17])=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:16])[CH3:15]
Reactant: C1CCNCC1
Reactant: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nn2ccccc2c1C(=O)C(C)N1CCCCC1
Product: Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of 500 mg (2 mmol) of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one, 478 ul (4.8 mmol) of piperidine and 50 mg of NaI in 4 ml of MeOH was stirred at 50° C. overnight. The residue obtained after evaporation of the solvent was purified on an Al2O3 column. The fractions containing purified product were titrated with 4N HCl-dioxane to obtain a precipitate. Recrystallization from isopropanol/ether produced 175 mg of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-(piperidin-1-yl)propan-1-one hydrochloride. Compound 1036.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[N+:14]([O-])([OH:16])=[O:15].O>C(OC(=O)C)(=O)C.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:11])=[O:10])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1ccc(NC(C)=O)cc1Br
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1Br
Temperature: 5 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a cold (5° C.) solution of 3.36 g (13.8 mmol) of 2-Bromo-4-acetaminoanisole in 5 mL of acetic anhydride and 10 mL of acetic acid, was added dropwise 0.9 mL (13.8 mmol) of concentrate nitric acid. The resulting solution was stirred at 5° C. for 3 h, poured into 90 mL of water, stirred, and filtered to collect the solid (the desired product). The solid was washed twice with cold water, dried under vacuo at 100° C., crystallized from chloroform to give 3.26 g (82% yield) of pure compound 6. 1H NMR (CDCl3) δ 10.2 (s, 1 H, NH), 9.09 (s, 1 H), 7.67 (s, 1 H), 3.95 (s, 3 H, OMe), 2.28 (s, 3 H, CH3).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH3:14])=[O:4].S(Cl)([Cl:20])(=O)=O.O>C(Cl)(Cl)Cl>[Cl:20][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[C:7]([CH3:14])[CH:8]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc(C)c(NC(=O)C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(NC(=O)C(F)(F)F)c(C)cc1Cl
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-Trifluoro-N-(5-methoxy-2-methylphenyl)acetamide (8.16 g) in chloroform (35 mL) was added sulfuryl chloride (3.12 mL) under ice-cooling, and the mixture was stirred overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the residue was added hexane, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with hexane, and then dried under reduced pressure to obtain the title compound (7.02 g). 1H-NMR (CDCl3) δ ppm: 2.23 (3H, s), 3.90 (3H, s), 7.24 (1H, s), 7.59 (1H, s), 7.60-7.82 (1H, br).
Reaction SMILES: B(O)O.[C:4]([CH:7]([CH:9](C(O)=O)O)O)(O)=O.[CH:14]([C:16]1[C@H:21]([C:22]([O:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[N:20]2[C:38](=[O:50])[C@@H:39]([NH:40][C:41](=[O:49])[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:19]2[S:18][CH:17]=1)=[O:15].O.C(OCC)(=O)C>O1CCCC1>[OH:15][CH:14]([C:16]1[C@H:21]([C:22]([O:24][CH:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:23])[N:20]2[C:38](=[O:50])[C@@H:39]([NH:40][C:41](=[O:49])[CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C@H:19]2[S:18][CH:17]=1)[CH2:9][CH:7]=[CH2:4]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: OBO
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC(O)C1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
via a tartrate boronate. A mixture of dimethyl (R,R)-2-allyl-1,3,2-dixoaborolane-4,5-dicarboxylate (0.67M in toluene, 1.8 ml, 1.2 mmol) and 0.4 nm molecular sieves (50 mg) was stirred at 20° C. for 10 minutes and then cooled to −70° C., and then a solution of diphenylmethyl (4R, 6R, 7R)-3-formyl-7-phenylacetamidoceph-2-em-4-carboxylate (100 mg, 0.2 mmol) in tetrahydrofuran (0.5 ml) was added dropwise. After 2 h at −70° C. the mixture was warned to 20° C. and water and ethyl acetate were added. The organic layer was dried (MgSO4) and evaporated and the residue purified by chromatography as in part a to give the title compound S-diastereomer, 45 mg (43%), and the R-diastereomer 8 mg (8%).
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11](O)=[O:12])=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.ClC([N:20](C)C)=C(C)C>C(Cl)Cl>[SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([NH2:20])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(S)n2ncc(C(=O)O)c2n1
Reactant: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: Cc1cc(S)n2ncc(C(N)=O)c2n1

Procedure:
A suspension of 105 g of 7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid in 400 ml of methylene chloride was treated with 6.3 ml of 1-chloro-N,N,2-trimethyl-1-propenamine and treated in an ultrasound bath until the majority has passed into solution. The mixture was suction filtered over a glass fiber filter, and ammonia was conducted into the clear filtrate at 20°. A crystalline precipitate formed which was filtered off under suction, dried and subsequently triturated in 100 ml of H2O for 5 minutes. The insoluble material was filtered off and the filtrate was concentrated in a vacuum to half of the volume. Upon allowing to stand at 0°, there was obtained 7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide as the ammonium salt in the form of white crystals.
Reaction SMILES: N#N.[F:3][C:4]1[CH:5]=[C:6]([C:10]2[O:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]([OH:18])=O)[CH:7]=[CH:8][CH:9]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:33]([Si:37]([CH3:54])([CH3:53])[O:38][CH:39]([C:41]1[O:42][C:43]([CH2:46][N:47]2[N:51]=[C:50]([NH2:52])[CH:49]=[N:48]2)=[CH:44][N:45]=1)[CH3:40])([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:33]([Si:37]([CH3:54])([CH3:53])[O:38][CH:39]([C:41]1[O:42][C:43]([CH2:46][N:47]2[N:51]=[C:50]([NH:52][C:16]([C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=3)=[O:18])[CH:49]=[N:48]2)=[CH:44][N:45]=1)[CH3:40])([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)o1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(N)n2)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c(-c2cccc(F)c2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid (34 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with HOBt (25 mg, 0.19 mmol), EDC (74 mg, 0.38 mmol), DMAP (5 mg, 0.04 mmol) and the resulting mixture was stirred at rt for 30 min. 2-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-ylamine (50 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the resulting mixture was stirred at rt for 16 h. CH2Cl2 (20 mL) followed by water (15 mL) were added and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 02: tR=1.22 min, [M+H]+=527.5.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:17](N1C=CN=C1)([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:18]>C(Cl)Cl>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][C:17]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:18])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)n1ccnc1
Temperature: 45 °C
Yield: 69.9 %

Procedure:
To a solution of 2-amino-5-chlorobenzophenone (40 g, 172.7 mmol) in CH2Cl2 (175 μL) was added carbonyldiimidazole (30.8 g, 189.9 mmol). The reaction was heated to 45° C. for 16 h resulting in a white precipitate. The reaction was cooled in an ice bath and the precipitate collected by vacuum filtration and dried to give 39.3 g (69.9%) of N-(2-benzoyl-4-chlorophenyl)-1H-imidazole-1-carboxamide as a white solid. 1H NMR (CDCl3, 400 MHz) 8.66 (s, 1H); 7.46 (m, 4H); 7.25 (s, 1H); 7.19 (d, J=6.96 Hz, 2H); 7.15 (s, 1H); 6.94 (m, 2H); 6.76 (d, J=2.29 Hz, 1H). MS (Electrospray): m/z 348.0 (M+Na).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@@H:17]([OH:19])[CH3:18])[CH2:8]1)[CH3:5])[CH3:2].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O>[C:35]([O:19][C@H:17]([C@@H:16]1[C@:20]2([CH3:28])[C@H:13]([C@H:12]3[C@H:23]([CH2:22][CH2:21]2)[C@:24]2([CH3:27])[C:9]([CH2:8][C@@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[CH2:26][CH2:25]2)=[CH:10][CH2:11]3)[CH2:14][CH2:15]1)[CH3:18])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)O)[C@@]4(C)CC[C@@H]32)C1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
iii)—A solution of (3β,20S)-3-[(1-ethoxyethyl)oxy]pregn-5-en-20-ol (compound 3a; 56.9 g) in a mixture of dry pyridine (144 ml) and acetic anhydride (72.4 ml) was stirred at room temperature for 18 h. Water (482 ml) was added and stirring was continued for another 1 h. The product was extracted into ethyl acetate; the combined organic phases were washed with a saturated aqueous solution of sodium hydrogen carbonate and with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,20S)-3-[(1-ethoxyethyl)oxy]pregn-5-en-20-ol acetate (compound 4a; 66.1 g) which was used in the following step without further purification.
Reaction SMILES: C[C@@H:2]([C:7]([N:9]1[C@H:13]([C:14](O)=O)[CH2:12][CH2:11][CH2:10]1)=O)CSN=O.C[C@@H](C(N1[C@H:27]([C:28](O)=O)[CH2:26][CH2:25][CH2:24]1)=O)CS.[N:31]([O-])=O.[Na+]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.S(=O)(=O)(O)O>[C:13]1([NH:9][CH2:7][CH2:2][NH2:31])[C:14]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=N[O-]
Reactant: C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O
Reactant: C[C@H](CSN=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NCCNc1cccc2ccccc12

Procedure:
Typical preparation of S-nitrosocaptopril involve the reaction of 50 mM captopril with 50 mM NaNO2 in 0.1N acetic or sulfuric acid at room temperature for five minutes, after which the reaction solution is passed over a cation exchange resin, e.g., Dowex 50 in the protonated form, and the product eluted with water. The fractions that give positive reactions with N-(1-naphthyl)ethylenediamine, after exposure to 0.15% HgCl2 and diazotization with sulfanilamide, are lyophilized. Hygroscopic, bright red crystals (m.p. 98°-104° C.) were obtained that were shown to be S-nitrosocaptopril by NMR in deuterated DMSO and by mass spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].[OH-:22].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:18][CH2:17][C:16]([O:20][CH3:21])=[O:22])([CH2:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])[C:4]=2[CH:3]=1
Reactant: [OH-]
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: C=CC(=O)OC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CCC1(CCC(=O)OC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reaction time: 8 h
Yield: 80 %

Procedure:
2,7-Dibromofluorene (1 g, 3.1 mmol), methyl acrylate (861 mg, 10 mmol) tetrabutylammonium bromide (100 mg, 0.3 mmol) and toluene (5 mL) were added to a small round bottom flask with a Teflon-coated stirbar. Next 2 mL of 50% NaOH (aq) is added while stirring. The reaction is allowed to proceed overnight. The next day the toluene layer is transferred to a flask and the aqueous layer extracted with two portions of toluene. The organic layers are combined, dried with Mg2SO4, and filtered. Silica (2 g) is added to the filtrate and the solution is evaporated. The product is obtained as a white solid (1.23 g, 80% yield) after purification by column chromatography.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([CH2:8][S:9]([O-:12])(=[O:11])=[O:10])[CH3:7].C(OP(Cl)(=O)[O-])C.[Cl:20][C:21]1[S:25]C(C=O)=[CH:23][CH:22]=1>C1COCC1.O>[CH2:1]([O:10][S:9]([CH:8]=[CH:6][C:7]1[S:25][C:21]([Cl:20])=[CH:22][CH:23]=1)(=[O:12])=[O:11])[CH3:2]
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(Cl)s1
Reactant: CCCS(=O)(=O)[O-]
Agent: CCOP(=O)([O-])Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOS(=O)(=O)C=Cc1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (53.1 mL, 2.5M solution in hexanes) is added dropwise to a solution of ethylmethanesulfonate (12.9 mL, 0.12 mol) in THF (300 mL) at −78° C. The reaction mixture is stirred for 15 min then ethylchlorophosphonate (9.9 mL, 0.07 mol) is added dropwise. The solution is stirred at −78° C. for 30 minutes and then heated to 50° C. for 1 hour. The reaction mixture is then cooled to −78° C. and stirred for 1 h then 5-chlorothiophenecarboxaldehyde (7.1 mL, 0.07 mol) is added dropwise. The reaction mixture is allowed to slowly warm to RT overnight. Water (30 mL) is added to the mixture and stirred for 15 min then concentrated in vacuo. The residue is taken up in CH2Cl2 and washed with water, brine, dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by column chromatography eluting with 5% EtOAc/hexanes to give title product (11.3 g, 0.04 mol) as an oil. 1H NMR (CDCl3, 300 MHz) δ7.51 (d, 1H), 7.10 (d, 1H), 6.91 (d, 1H), 6.42 (d, 1H), 4.20 (q, 2H), 1.40 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:23][CH:10]1OC(=O)C1C=CC([N+]([O-])=O)=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N:52]([C:55]1[N:63]=[C:62]([F:64])[N:61]=[C:60]2[C:56]=1[NH:57][CH:58]=[N:59]2)=[N+:53]=[N-:54]>ClCCCl.ClCCl>[N:52]([C:55]1[N:63]=[C:62]([F:64])[N:61]=[C:60]2[C:56]=1[N:57]=[CH:58][N:59]2[C@@H:10]1[O:23][C@H:24]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:53]=[N-:54]
Reactant: [N-]=[N+]=Nc1nc(F)nc2nc[nH]c12
Reactant: O=C(OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: [N-]=[N+]=Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.6 %

Procedure:
A solution of 2,3,5-tri-O-benzyl-1-α-D-arabinofuranosylchloride (freshly prepared from 1.9 g of 2,3,5-tri-O-benzyl-1-O-p-nitrobenzoyl-D-arabinofuranose), N,N-diisopropylethylamine (0.58 mL) and 6-azido-2-fluoropurine (0.50 g) in 10 mL of anhydrous 1,2-dichloroethane was heated at reflux overnight. Additional N,N-diisopropylethylamine (0.26 mL) was added and heating was continued for an additional 24 hours. The mixture was cooled to ambient temperature and diluted with dichloromethane (60 mL) and washed sequentially with 10% aqueous sodium hydroxide (NaOH), water, 1N phosphoric acid (H3PO4), saturated NaCl and then dried over MgSO4 along with decolorizing carbon. The dried solution was filtered through celite and concentrated in vacuo. The residue was purified by silica gel chromatography with gradient elution from 3:1 Hexane:ethyl acetate to 100% ethyl acetate to obtain 0.40 g of the title compound as a colorless oil; IR (neat) 3031, 2922, 2867, 2126, 1608 cm-1 ; 1H NMR (DMSO-d6, 360 MHz) δ3.65-3.75 (m, 2H), 4.16 (q, J=5 Hz, 1H), 4.22 (d, J=11.8 Hz), 4.42 (t, J=5.5 Hz, 1H), 4.47 (d, J=11.8 Hz, 1H), 4.51 (s, 2H), 4.58 (t, J=5.5 Hz, 1H), 4.62 (d, J=12.0 Hz, 1H), 4.68 (d, J=12.0 Hz, 1H), 6.41 (d, J=5.5 Hz, 1H), 6.9-6.95 (m, 2H) 7.1-7.2 (m, 3H), 7.25-7.4 (m, 10H), 8.48 (s, 1H); UV (MeOH) λmax, 286 nm; MS (EI+, m/z) 582 (M+H)+.